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A5288 was an open-label phase IV, prospective interventional, strategy study in resource-limited settings (RLS) for HIV-1 infected participants with triple-class experience or resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), and protease inhibitors (PIs) and who were failing their current regimen. The use of novel agents and contemporary clinical decision management tools that include standard genotyping and plasma HIV viral load (VL) monitoring were evaluated. The screening genotype results and antiretroviral (ARV) history were used to allocate potential participants to one of four Cohorts (A, B, C or D) and to select an associated ARV regimen based on the Cohort assignment. In brief, individuals assigned to Cohort A continued on the same PI as in their second-line regimen, with the ability to modify NRTIs. Those assigned to Cohort B who were negative for hepatitis B were randomized to receive RAL and DRV/RTV with either the best available NRTIs (Cohort B1) or ETR (Cohort B2). If they were positive for hepatitis B they were assigned to Cohort B3 and received RAL, DRV/RTV and either FTC/TDF or 3TC/TDF. Individuals assigned to Cohort C received RAL and DRV/RTV with the best available NRTIs. Those ineligible for Cohorts A, B or C were assigned to Cohort D and received the best available regimen that included study provided drugs and any locally provided drugs.

At sites where feasible and relevant, the study evaluated an adherence support intervention. This involved a randomized comparison of a cell phone-based adherence support intervention plus local standard-of-care adherence support procedures (CPI+SOC) versus the SOC adherence support procedures.

Participants enrolled to the study in Step 1. If a participant experienced a confirmed virologic failure (defined as two consecutive HIV-1 RNA measures >= 1000 copies/mL) at/after 22 weeks on their Step 1 regimen, they had another genotype test performed and cohort/regimen selected for Step 2. With the exception of one additional visit 4 weeks after enrollment to Step 2, the visit schedule for Step 2 followed the participant's original Step 1 schedule throughout the remainder of follow up.

Participants were followed in Steps 1 and 2 until 48 weeks after the last participant was enrolled to Step 1. During the first 48 weeks after Step 1 enrollment, clinic visits occurred at weeks 4, 12, 24, 36 and 48. After week 48, visits occurred every 12 weeks for adherence, safety and efficacy measures.

Participants had a final step 1/2 visit between November 22, 2016 and February 13, 2017. At the final step 1/2 visit, participants taking RAL, ETR, or DRV who were unable to obtain these drugs locally (e.g., through local treatment programs), and were otherwise eligible, entered Step 3 and continued to receive these drugs through the study for up to 96 additional weeks. Step 3 is no longer enrolling. Step 3 follow up is ongoing.

The primary analysis specified in the protocol and in the Statistical Analysis Plan was to estimate the proportion of participants in the overall study population who were virologically suppressed (HIV-1 RNA ≤200 copies/mL) at week 48 with a 95% confidence interval. Secondary outcome results will be provided in a future submission (December 2018). The results currently submitted only pertain to Step 1 and 2 follow up.

No LPV/RTV resistance and susceptible to at least one NRTI, regardless of NNRTI resistance or prior RAL exposure

• Continue second-line regimen which may include LPV/RTV; NRTIs could be modified

Changed under LOA#3 to:

No LPV/RTV resistance and susceptible to at least one NRTI, regardless of NNRTI resistance or prior RAL exposure

• Continue PI backbone; NRTIs could be modified. If on a RAL-containing regimen, RAL must be discontinued.

Drug: Second line ART regimens - based on a boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs)

LPV/r and ATV/r were the preferred bPIs for second-line ART. TDF + (3TC or FTC) or AZT + 3TC were the most frequent NRTI backbones. Cohort A did not include any of the new drugs; therefore, it is distinct from Cohorts B, C, and D.

Other: SOC adherence versus SOC+CPI adherence

not participating in the adherence randomization; OR

randomized to SOC adherence; OR

randomized to SOC+CPI adherence.

Experimental: Sub-cohort B1

Under Protocol version 1.0:

Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and without active hepatitis B infection at screening

• Best available NRTIs, RAL, & DRV/RTV

Changed under LOA#2 to:

Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (and without active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (and without active hepatitis B infection at screening)

• Best available NRTIs, RAL, & DRV/RTV

Drug: Darunavir

Participants were administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (taken with Ritonavir 100 mg twice a day [200 mg per day])

Other Names:

DRV

Prezista

Drug: Raltegravir

Participants were administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food

Other Names:

RAL

Isentress

Other: SOC adherence versus SOC+CPI adherence

not participating in the adherence randomization; OR

randomized to SOC adherence; OR

randomized to SOC+CPI adherence.

Experimental: Sub-cohort B2

Under Protocol version 1.0:

Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and without active hepatitis B infection at screening

• ETR, RAL, and DRV/RTV

Changed under LOA#2 to:

Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (and without active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (and without active hepatitis B infection at screening)

• ETR, RAL, and DRV/RTV

Drug: Darunavir

Participants were administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (taken with Ritonavir 100 mg twice a day [200 mg per day])

Other Names:

DRV

Prezista

Drug: Etravirine

Patients were administered Etravirine orally as two 100 mg tablets or one 200 mg tablet twice a day (400 mg per day) following a meal.

Other Names:

ETR

Intelence

Drug: Raltegravir

Participants were administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food

Other Names:

RAL

Isentress

Other: SOC adherence versus SOC+CPI adherence

not participating in the adherence randomization; OR

randomized to SOC adherence; OR

randomized to SOC+CPI adherence.

Experimental: Sub-cohort B3

Under Protocol version 1.0:

Susceptible to DRV/RTV and ETR with or without resistance to NRTIs (and may have resistance to other PIs) and with active hepatitis B infection at screening

• RAL, DRV/RTV, and FTC/TDF or TDF+3TC

Changed under LOA#2 to:

Resistance to LPV/RTV but susceptible to DRV/RTV and ETR and with no prior RAL exposure and regardless of NRTI resistance (with active hepatitis B infection at screening) OR Resistance to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and ETR and with no prior RAL exposure (with active hepatitis B infection at screening)

• RAL, DRV/RTV, and FTC/TDF or TDF+3TC

Drug: Darunavir

Participants were administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (taken with Ritonavir 100 mg twice a day [200 mg per day])

Other Names:

DRV

Prezista

Drug: Emtricitabine/tenofovir disoproxil fumarate

Patients were administered FTC/TDF orally as one fixed dose combination tablet (FTC 200 mg/TDF 300 mg) once daily, with or without food.

Other Names:

FTC/TDF

Truvada

Drug: Raltegravir

Participants were administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food

Other Names:

RAL

Isentress

Other: SOC adherence versus SOC+CPI adherence

not participating in the adherence randomization; OR

randomized to SOC adherence; OR

randomized to SOC+CPI adherence.

Experimental: Cohort C

Under Protocol version 1.0:

Resistance to NRTIs and ETR or resistance to ETR alone (and may have resistance to PIs other than DRV)

• Best available NRTIs, RAL, and DRV/RTV

Changed under LOA#2:

Resistance to LPV/RTV and ETR but susceptible to DRV/RTV and with no prior RAL exposure and regardless of NRTI resistance OR Resistance to ETR and to all NRTIs (i.e. susceptible to none) but susceptible to DRV/RTV and with no prior RAL exposure

• Best available NRTIs, RAL, and DRV/RTV

Drug: Darunavir

Participants were administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (taken with Ritonavir 100 mg twice a day [200 mg per day])

Other Names:

DRV

Prezista

Drug: Raltegravir

Participants were administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food

• Best available regimen, including study-provided and any locally available drugs

Changed under LOA#2:

Not eligible for Cohort A, B, or C:

• Best available regimen, including study-provided and any locally available drugs

Updated under protocol v2.0:

• Best available ART regimen, including study-provided and any locally available non-experimental drugs

Drug: Study provided drugs according to patient resistance profile (DRV, ETR, RTV, FTC/TDF) + any in country available drug as applicable & available

For Cohort D, in many situations a participant received the same regimen that patients are getting in Cohorts B and C if that was the best combination that can be obtained according to his/her resistance profile and drug availability (as for many countries there were no further drug options beyond the available study drugs).

Proportion of Participants With Plasma HIV-1 RNA ≤200 Copies/mL at 48 Weeks [ Time Frame: 48 weeks after the date of entry ]

The measurement closest to exactly 48 weeks (ie, 7x48=336 days) after the date of entry, within the window of 48 weeks ± 6 weeks (specifically 295 to 378 days after randomization, inclusive).

The analysis in the protocol and in the Stat. Analysis Plan involved estimating the proportion of participants in the overall study population with HIV-1 RNA ≤200 copies/mL at week 48 with a 95% confidence interval calculated via a Wald approach. Death or lost to follow-up before week 48 was considered as HIV-1 RNA>200 copies/mL at week 48. Missing results at week 48 were considered as HIV-1 RNA >200 copies/mL at week 48 unless the immediately preceding and succeeding HIV-1 RNA measurements were ≤200 copies/mL. Since the primary analysis was on the total study population, overall results were also submitted. All participants in B3 had HIV-1 RNA ≤200 copies/mL at week 48. Therefore, Wald confidence interval could not be computed for B3 and Clopper-Pearson Exact confidence interval is provided.

Time to Confirmed VF Defined as First HIV-1 RNA >1000 Copies/mL at or After 24 Weeks. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ]

The VF has to be confirmed by the next HIV-1 RNA measurement also being >1000 copies/mL (irrespective of the time between the initial and confirmatory measurements provided that they are obtained on different days, and irrespective of ART being received at the times of these measurements). For the purposes of this outcome measure, a week 24 measurement includes any HIV-1 RNA measurement obtained at ≥7*22=154 days after randomization (to allow for the protocol-defined 14 day window for scheduling the week 24 visit)

Secondary outcome measures will be entered by December 2018.

Time to Confirmed VF Defined as First HIV-1 RNA >1000 Copies/mL at or After 24 Weeks With a New Resistance-associated Mutation Detected in Population-based Sequencing. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ]

The new resistance-associated mutation is defined as one not present in the last population-based sequence obtained prior to randomization

Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)

Secondary outcome measures will be entered by December 2018.

Time From Randomization to Death. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ]

Secondary outcome measures will be entered by December 2018.

Time From Randomization to the First of Death, an AIDS-defining Event or a Non-AIDS-defining Event. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ]

Secondary outcome measures will be entered by December 2018.

Time From Randomization to the First of Death or Hospitalization. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ]

Secondary outcome measures will be entered by December 2018.

Time From Randomization to Treatment Modification or Discontinuation. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ]

Treatment modification is defined as the first occurrence of a substitution or subtraction of one or more drugs in the study regimen or of the addition of a new drug. This would not include splitting any fixed dose combination medications if the participant continues on the active drugs of the combination.

Secondary outcome measures will be entered by December 2018.

Time From Randomization to Treatment Modification or Discontinuation Due to Toxicity. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ]

Secondary outcome measures will be entered by December 2018.

Change From Baseline in Fasting Values of Total Cholesterol at Week 24, 48 and 72. [ Time Frame: Baseline to week 24, 48 and 72 ]

Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A) Secondary outcome measures will be entered by December 2018.

Change From Baseline in Fasting Values of HDL-C at Week 24, 48 and 72. [ Time Frame: Baseline to week 24, 48 and 72 ]

Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A)] Secondary outcome measures will be entered by December 2018.

Change From Baseline in Fasting Values of Calculated LDL-C at Week 24, 48 and 72. [ Time Frame: Baseline to week 24, 48 and 72 ]

Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A) Secondary outcome measures will be entered by December 2018.

Change From Baseline in Fasting Values of Triglycerides at Week 24, 48 and 72. [ Time Frame: Baseline to week 24, 48 and 72 ]

Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A) Secondary outcome measures will be entered by December 2018.

Change From Baseline in Fasting Values of Glucose at Week 24, 48 and 72. [ Time Frame: Baseline to week 24, 48 and 72 ]

Baseline is defined as the last measurement obtained on or before the earlier of the following two dates: the date of randomization plus three days (this is the time allowed in the protocol for starting study-defined ART) and the date of starting the study-defined ARV regimen (this second date applies only to Cohorts B, C and D as there is no change of regimen for patients in Cohort A) Secondary outcome measures will be entered by December 2018.

Time From Randomization to the Development of IRIS. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ]

Secondary outcome measures will be entered by December 2018.

Time to First Dose Modification Due to Grade 3 or 4 Toxicity. [ Time Frame: Throughout study; participants are expected to be followed for an average of 84 weeks ]

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria for Step 1:

HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA VL.

Any previous combination of ARV treatment at any time with at least one regimen that contained one NNRTI and two NRTIs which was replaced with a PI-based regimen because of virologic, immunologic, or clinical treatment failure, or because of toxicity.

NOTE: All potential participants with prior RAL exposure were assigned to either Cohort A or Cohort D.

At screening, receipt of a PI-based regimen with no regimen change for a minimum of 24 weeks prior to screening.

Confirmation of VF of current second-line PI-based ART. NOTE A: Failure of the current second-line regimen was defined as two consecutive measurements of plasma HIV-1 RNA ≥1000 copies/mL obtained at least 1 day apart while on the current PI-based regimen. "Current PI-based regimen" and "current regimen" were understood to be the regimen described (ie, the regimen that the candidate was taking when the first VF sample was drawn plus only those modifications allowed).

CD4+ T-cell count result from a specimen drawn within 103 days prior to study entry

Hepatitis B panel that includes HbsAB, HBcAB, and HBsAG or only HBsAG, with plasma stored for later anti-HBs and anti-HBc.

NOTE A: Candidates who were eligible for cohort B and who were positive for active hepatitis B infection were assigned to sub-cohort B3 at registration/randomization.

NOTE B: Candidates with CrCl <60 mL/min who were also positive for active hepatitis B infection were not eligible.

Females of reproductive potential (women who have not been post-menopausal for at least 24 consecutive months, ie, who have had menses within the preceding 24 months, or women who have not undergone surgical sterilization, hysterectomy or bilateral salpingectomy or bilateral oophorectomy or tubal ligation) must have had a negative serum or urine pregnancy test prior to the submission of the screening genotype testing sample and again within 48 hours prior to randomization or registration.

Female participants of reproductive potential must have agreed not to participate in the conception process (ie, active attempt to become pregnant, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the female participant must have used at least one reliable form of contraceptive. Female participants must have continued to use contraceptives while receiving study treatment and for 6 weeks after stopping study treatment.

Acceptable forms of contraceptives included:

Condoms (male or female) with or without a spermicidal agent

Diaphragm or cervical cap with spermicide

Intrauterine device (IUD)

Hormonal contraception

Female participants who were not of reproductive potential or whose male partner(s) had documented azoospermia) were not required to use contraceptives. Any statement of self-reported sterility or that of her partner's must have been entered in the source documents.

NOTE: Acceptable documentation of lack of reproductive potential was oral or written documentation from the participant.

Ability and willingness of potential participant to provide informed consent.

Willingness of potential participant to adhere to protocol requirements, especially with respect to treatment assignment and ability to obtain non-study provided ART, if needed.

Ability to take oral study medications.

No intention of permanent relocation that would preclude attending Step 1 and 2 study follow-up visits.

Availability of a successful, interpretable resistance genotype report from a DAIDS-approved regional genotyping facility from testing performed on a plasma sample that was collected during screening (ie, at or after the date that a sample is collected to confirm HIV-1 virologic failure) and which was shipped to a regional resistance testing laboratory once documentation of two screening plasma HIV-1 RNA values ≥1000 copies/mL were available.

Identification of a cohort assignment and ARV regimen for use on study, selected from the recommended options provided by the site investigator, and reviewed and approved by the A5288 Clinical Management Committee (CMC).

Exclusion Criteria for Step 1:

Pregnancy or breast-feeding.

Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.

Active drug or alcohol use or dependence that, in the opinion of the site investigator, would have interfered with adherence to study requirements.

Serious illness requiring systemic treatment and/or hospitalization until candidate either completes therapy or was clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry.

Concurrent illness or condition that would compromise the ability to take study medication, follow the protocol, or that would make participation not in the best interest of the participant, per the site investigator.

Requirement for taking any of the prohibited medications with the selected ARV study regimen, or within 14 days prior to study entry.

NOTE: Study candidates should not have discontinued any component of their ART during screening. The 14-day restriction on prohibited medications did not apply to ARVs.